Microbiomics is taking a sharp turn. Until now, the field was limited to fecal transplants from healthy patients to those with gut conditions. The transplant is an awkward procedure that also creates regulatory and other challenges. But as the field has progressed, companies today are pushing forward to adapt technologies and therapeutics to more practical forms, such as microbial nucleic acid-based signatures from liquid biopsies and therapeutics that can be safely taken by mouth.
“The rise in products that don’t use feces or transplantation is the most notable trend,” says Mollie Roth, JD, managing partner at PGx Consulting, and founder and chair of the Arrowhead Translational Microbiome Conference.
And it’s a growing field. The world market for microbiome-related products is expected to double, from about $942 million to just over $173 million, over the next five-to-ten years, with more than a dozen microbiome-related products in development. But, notably, only a handful have reached later phases yet.
“The microbiome-can have an impact in a very wide range of conditions,” says Mark Fitzgerald, an IP attorney at general practice law firm Nixon Peabody LLP. “Everything from gut infections, to cancers, and neurological conditions are impacted by microbes in the gut.” It’s a whole new world for biomedical researchers to explore. The FDA, Fitzgerald points out, is also learning about this growing field, which adds to the uncertainty.
Initially, when microbiome-related therapies began making inroads, there were major questions about how intellectual property would be sorted out. “Our firm files a lot of microbiome-related patents,” says Fitzgerald. One challenge is that U.S. case law does not allow patenting of products of nature. “Plus, you can’t just describe what it is, you have to describe how it works too,” he adds. Another potential problem is that for any given microbe, you can find more, possibly many more, bugs that do the same thing.
Fitzgerald recently co-authored a review of “Microbiome therapeutic and patent protection,” (Fitzgerald and Spek, Nature, July 2020). He and his associate describe three large subsets of microbiome product subtypes, based on ‘bug status.’ Those categories are: ‘drugs from bugs,’ ‘drugs for bugs,’ and ‘bugs as drugs.’
The further subcategories within ‘bugs as drugs,” the two lawyers say, differ substantially from each other and have unique patentability challenges, as demonstrated by the lead products now. Rebiotix’s RBX2660 is an enema product that was recently found efficacious in a randomized, double-blind, Phase II trial for recurrent Clostridium difficile infection (CDI). Finch Therapeutics’ CP-101, meanwhile, is a lyophilized fecal matter composition for oral administration and now in Phase II for treatment of CDI. And Seres Therapeutics’ SER-109 is a type of FMT but it is based on spore-forming bacteria isolated from fecal matter.
Within this area and others, companies are staking their IP claims. “The case law is being worked out, and it is much clearer now than it was a few years ago,” says Phil Strandwitz, co-founder and CEO of Holobiome, a microbiome therapeutics company based in Cambridge, MA.
Lead products and new trends
A recent high point for the field was the release of preliminary results from Seres’ SER-109, a capsule of live bacteria that is on track to become the first approved microbiome-related therapy. The pivotal study, which was in C. difficile and called Ecospor III, met its primary endpoint by reducing infection recurrence at eight weeks by 30.2% versus placebo. Overall risk of recurrence was cut by 83%.
On a conference call announcing the results, Seres’ CEO Eric Shaff said the data represent a “critical moment” for his company. This accomplishment is especially notable since SER-109 had failed in Phase II. Possible reasons for that failure ranged from manufacturing problems through clinical site variability to even a mix-up of trial samples. Ultimately Ecospor III tested a 10-fold higher SER-109 dose than was used in Phase II.
Rebiotix, a Ferring company, is advancing RBX2660 from their Microbiota-Based Therapies (MRT) drug platform. In May of this year, the company announced the first positive preliminary results from a Phase II clinical trial of the drug, Phase III results are expected next year.
While these companies are showing positive results in the clinic, there are other encouraging signs the field is maturing, and branching into other therapeutic areas such as oncology.
Micronoma recently launched with $3 million in seed financing. The company is described as the “First early cancer-detection company to use microbial biomarkers in diagnostics,” in an August 11 press release. In that release, they also reported their technology has “shown that distinct cancer types can be diagnosed sensitively and specifically solely using microbial nucleic acids in blood and tissue.”
CEO and co-founder Sandrine Miller-Montgomery was previously executive director of the Center for Microbiome Innovations. Her co-founders are also leaders in the field: Rob Knight, director of the Center for Microbiome Innovation at the University of California San Diego, and Greg Poore, an M.D.-Ph.D. candidate at UC San Diego School of Medicine and the company’s chief analytics officer.
Micronoma’s approach is to use machine learning on microbial genomic data to find novel diagnostics. Their platform was first demonstrated on The Cancer Genome Atlas Program (TCGA) database. The researchers re-examined whole-genome and whole transcriptome sequencing data from >10,000 patients with just over 30 different cancer types (Poore et al. Nature 2020) for microbial reads. They found unique microbial signatures in tissue and blood within and between most major types of cancer. These blood signatures remained predictive when applied to patients with stage Ia-IIc cancer and cancers lacking genomic alterations.
“Our signatures separate samples from people with cancer out from those of healthy people,” says Miller-Montgomery. “Certain signatures can also distinguish between types of cancer.” The signatures all involve targeted areas of the microbial genome, which is less expensive than using whole-genome sequencing. The platform compriseds of next-generation sequencing tools and reagents that are already being used for approved tests. “It’s never smart to reinvent the wheel,” notes Miller-Montgomery.
Micronoma’s method should be applicable to any malignancy, but the team will focus first on lung cancer. The goal is to have a cancer test in the clinic within the next two years, so there is plenty to do. “The Nature paper came out in mid-March, and that was just at the beginning of the shutdown,” says Miller-Montgomery. She and her colleagues are now working on filling out their leadership ranks, the rest of the team, and establishing a CLIA-certified lab.
Holobiome was founded by Northeastern University scientists studying the microbiome’s affects in the gut-brain axis, which comprises bidirectional communication between the central and the enteric nervous system, thereby linking parts of the brain with peripheral intestinal function. These links are through neural, endocrine, immune, and humoral channels.
The company recently announced a new research collaboration with Johnson & Johnson Consumer Inc. focused on developing proprietary bacterial products to treat digestive disorders. Holobiome will receive an upfront payment, plus additional payments contingent upon completing developmental milestones. This follows a similar agreement announced in January of 2018, which focused around developing microbiome therapeutics for sleep disorders and related comorbidities.
The company is pursuing patents aggressively, according to Strandwitz. Their programs are in pain, intestinal motility, and mood, with two areas still not disclosed.
Five-year-old, Denver-based microbiome therapeutics company The BioCollective is probably reaching the highest, literally, as they are interested in neurological targets including Parkinson’s disease and multiple sclerosis (MS). The company has focused first, however, on building a comprehensive platform to support collection of better microbiome samples and to promote development of related tools. It is developing products and services including reference samples, clinical trial collection services, “ick-free” sample collection kits, and a fecal sample bank. The firm’s leadership includes Martha Carlin, founder and chief executive revolutionary and Raul Cano, Ph.D., and CSO.
Their interest in neurologic disease research began in part because of the observation that some patients with certain conditions, including Parkinson’s and MS, report chronic constipation, which is likely due to impaired gut motility.
“The first paper on Parkinson’s and the microbiome came out in 2014,” Carlin says. Her husband has the condition and she was interested in looking for treatments. “My background is in turning around businesses,” she says. “So I put on that hat to address Parkinson’s.”
Realizing that having well designed reference tools would advance research more quickly, the company refined the tools and built up their databanks. “The quality control and advancing the science have been a big part of our focus,” Carlin says. The group has pursued large scale metagenomic sequencing of the microbiome and developed proprietary metabolic and enzymatic models based on that data. One goal is to create products such as food supplements that act through the microbiome.
An inviting path
Many microbiome players see open avenues ahead. With products getting closer to market, there will be more patent disputes and decisions, thereby mapping out the intellectual property landscape.
“The most significant hurdle now, during COVID-19, is getting big enough cohorts of the right types of patients for these studies,” says Miller-Montgomery. PGx Consulting’s Roth, meanwhile, points to the need to scale manufacturing and production of live bacteria, which has only ever lent itself to small scale production.” And these developers will need to ensure both quantity and viability of these products.
The most promising indications now are “Anything inflammatory bowel disease or C. difficile, but there is also some interesting work going on in Parkinson’s and autism,” says Roth. Another area that’s buzzing is “The intersection of the microbiome and immune oncology in terms of PDL1 and metastatic kidney cancer,” she adds, “and there is also some interesting work going on in Parkinson’s and autism.”
Not surprisingly, there is also some microbiome-related work on COVID-19 also arising [See sidebar below]. The pandemic has also had an impact on financing, of course. “Our Nature paper went out in March, and for the first few weeks after that COVID-19 was all investors wanted to talk about. But now we are finding that people are making the time and they want to hear what we have to say,” explains Micronoma’s Miller-Montgomery.
For hard-to-study conditions, such as Parkinson’s, there is also always the pressure to raise funding. “There is not significant funding for large-scale microbiome collection, but that’s what’s going to push the field ahead,” says Carlin. BioCollective’s Cano is also optimistic. “We are entering a growth phase,” he says. “We are growing exponentially in practice, application, and knowledge.”
Turning to the Pandemic
Besides making it harder to recruit subjects for trials, the COVID-19 pandemic has disrupted the investment landscape.
There is a role for the microbiome in the crisis, however. It’s thought that COVID-19’s high mortality is due in part to the hyperinflammatory response in the respiratory system and cytokine storm syndrome triggered by uncontrolled activation of the immune system. Some companies have jumped on the opportunity.
“We have a COVID-19 study underway for one of our assets,” says Adrian Murray, General Counsel at 4D Pharma PLC. The company’s initial plan was to focus on cancer, specifically immuno-oncology. But the company also had a candidate molecule (MRx-4DP0004) against airway inflammation and a speedy path to market. “We submitted the proposal in February and by April had approval to start the study,” Murray says.
On April 20 it received expedited acceptance from the UK Medicines and Healthcare products Regulatory Agency (MHRA) to begin a Phase II study of MRx-4DP0004 (a live biotherapy and targeted immunomodulatory treatment) in up to 90 patients with COVID-19. This study will compare the candidate drug to a placebo. Patients will also receive standard of care.
In a company press release, the study’s lead investigator, Dinesh Saralaya, was quoted as saying: “As well as its appropriate mechanism of action, the highly favorable safety profile of MRx-4DP0004 makes it a particularly attractive candidate for COVID-19 patients, and may potentially allow us to prevent or delay their progression to requiring ventilation and intensive care.”
In addition, scientists at the Center for Microbiome Innovation (CMI) at UC San Diego are working on a project to characterize the longitudinal progression of COVID-19 in patients at a local hospital. Thanks to that research, the center’s researchers have studied these patients’ microbiomes and viral information. This work is preliminary, but the team reported they are seeing a relationship in the microbiome of COVID-19 patients, whether or not they are symptomatic or asymptomatic.